Intellectual disability and neurogenesis defects associated with increased turnover of an O-GlcNAcase variant
Authier, F.; Attianese, B.; Galan Bartual, S.; Mitchell, C. W.; Ferenbach, A. T.; Doummar, D.; Charles, P.; Mignot, C.; Keren, B.; van Aalten, D.
Show abstract
Rare, high-impact genetic variants affecting genes essential for neurodevelopment represent a major contributing factor to uncharacterised intellectual disabilities. We present the first cases, population-based genetic evidence, an animal model and electrophysiological/functional dissection of pathogenic variants in OGA, a key regulator of protein O-GlcNAcylation, associated with cognitive and motor impairments. For a missense variant in the OGA C-terminal HAT domain, a dosage effect in genome-edited mouse embryonic stem cells is associated with impaired neuronal maturation. Mice harbouring this variant display altered brain OGA levels, while maintaining protein O-GlcNAcylation homeostasis. Hippocampal neurons exhibit altered developmental trajectories of neuronal network activity, mechanistically linked to pathways involved in synapse structure and function. We establish OGA variants as a cause of intellectual disability and show that partial reduction of OGA levels, even in the absence of global O-GlcNAc perturbation, impairs neuronal maturation and circuit function, highlighting a dosage-sensitive role for OGA in human neurodevelopment.
Matching journals
The top 10 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding 95%
- Familial ALS/FTD-associated RNA-Binding deficient TDP-43 mutants cause neuronal and synaptic transcript dysregulation in vitro 95%
- Specific OCRL1 patient mutations differentially impact Lowe Syndrome cellular phenotypes 94%
Similar papers in this journal
- Rapid degradation of Histone Deacetylase 1 (HDAC1) reveals essential roles in both gene repression and active transcription 94%
- CMTR1 is recruited to transcription start sites and promotes ribosomal protein and histone gene expression in embryonic stem cells 94%
- Separation of telomere protection from length regulation by two different point mutations at amino acid 492 of RTEL1 94%
Similar papers in this journal
- Novel genetic features of human and mouse Purkinje cell differentiation defined by comparative transcriptomics. 94%
- D-cysteine is an endogenous regulator of neural progenitor cell dynamics in the mammalian brain 94%
- The proteasome regulator PI31 is required for protein homeostasis, synapse maintenance and neuronal survival in mice 94%
Similar papers in this journal
- A transgenic line that reports CSF1R protein expression provides a definitive marker for the mouse mononuclear phagocyte system 93%
- Vitamin D regulates MerTK-dependent phagocytosis in human myeloid cells 92%
- Conserved epigenetic programming and enhanced heme metabolism drive memory B cell reactivation 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.